The present invention is a method and formulations using chondroitinase AC and chondroitinase B, glycosaminoglycan degrading enzymes, to inhibit tumor cell growth, metastasis and angiogenesis, and thereby to treat or prevent certain cancers.
Proteoglycans on the cell surface and in the extracellular matrix contain variable glycosaminoglycan chains, which include heparan sulfate and chondroitin sulfates A, B, or C. While some proteoglycans contain only one type of glycosaminoglycan, others contain a mixture of heparan and chondroitin sulfates (Jackson et. al., Physiol. Rev. 71:481–530, 1991). Extracellular proteoglycans form a structural framework for cells and tissues, and together with cell-associated proteoglycans, have major functions in regulating cell adhesion, migration, and proliferation. Disruption of the normal synthesis and function of proteoglycans is thought to have an important role in tumor cell metastasis.
Tumor metastasis is the process by which malignant cells from a tumor spread throughout the body and develop into multiple secondary tumors (Lida et. al. Sem. Cancer Biol. 7:155–162, 1996; Meyer and Hart Eur. J. Cancer 34:214–221, 1998). In order to spread to other parts of the body, tumor cells must escape from the primary or original tumor, enter the blood stream or lymphatic system, and from there invade the tissue of other organs, where they multiply and form new tumors. Escape from the primary tumor and invasion into other organs is a complex multi-step process. Metastasis involves changes in tumor cell adhesion and motility, secretion of proteolytic enzymes, chemoattractants, and proteoglycans. In addition to these tumor cell activities, angiogenesis, or the formation of new blood vessels, is also a vital step in the metastatic process (Folkman Nature Medicine 1:27–31, 1995).
The involvement of different types of glycosaminoglycans in tumor cell metastasis has been investigated. Heparan sulfates on the cell surface appear to inhibit cell motility (Culp et. al. J. Cell Biol. 79:788–801, 1978). Heparan sulfates in the extracellular matrix act to impede cell movement through the formation of a tight network with other matrix components. Tumor cells can secrete a glycosaminoglycan-degrading enzyme, heparanase, which cleaves heparan sulfates and enhances escape from the tumor and promotes metastasis (Culp, et al. J. Cell Biol. 79:788–801, 1978; Nakajima et. al. Science 220:611–613, 198).
In contrast, chondroitin sulfates have never been linked to an enhancement of motility of both endothelial and tumor cells (Culp et. al. 1978). When formation of chondroitin sulfate proteoglycans is inhibited by treating cells with -xylosides, motility, migration and the ability to invade matrix material are inhibited (Henke et. al., J. Clin. Invest. 97:2541–2552, 1996; Faassen et. al., J. Cell Biol. 116:521–531, 1992 and Trochan et. al. Int. J. Cancer 66:664–668, 1996). Removal of chondroitin sulfates from the cell surface with chondroitinase ABC also decreases cell motility (Faassen et. al., 1992); however the effects of this enzyme on invasion or metastasis, or on angiogenesis are not known.
It is an object of the present invention to provide methods for treating or preventing tumor growth, metastasis or angiogenesis.
It is a further object of the present invention to provide formulations for treating or preventing tumor growth, metastasis or angiogenesis.